DE 1 204 363 describes a medicament comprising a core with various layers applied thereto. The first (inner most) layer is soluble in the stomach, but insoluble in the intestine. The second protective layer is water soluble (independent of the pH value) and the third (outer most) protective layer is a gastric juice-resistant coating. However, this formulation is not suitable for Omeprazole because it only dissolves slowly in the intestine. However, a fast dissolution in the intestine is essential for the desired bio-availability.
EP 0 247 983 discloses a pharmaceutical agent for oral administration which comprises Omeprazole as an effective component. The core material contains Omeprazole together with an alkaline reacting compound or an Omeprazole salt, optionally together with an alkaline reacting adjuvant. Intermediate layers which form a separation layer between the alkaline reacting core and an outer layer of a gastric juice-resistant coating comprise water-soluble tablet carrier mediums or tablet carrier mediums quickly disintegrating in water or polymeric, water-soluble, film-forming substance mixtures which optionally contain buffering, alkaline compounds and which should capture protons penetrating from the outside. Aside from its water-solubility, the layer material is chemically and physically inert.
However, with use of an alkaline buffering substance, such as sodium acetate for example, this freely diffuses into the intermediate layer and penetrates into the outer gastric juice-resistant layer. The increase of the pH value associated therewith can favour the penetration of moisture through the enteric layer as a result of the increasing solubility. This means that the danger exists with the penetration of higher concentrations of protons that these reach the core and destroy the Omeprazole there. This last phenomena can easily occur especially when the outer gastric juice-resistant layer possesses faults as a result of imperfections which can arise in production, physical load or through ageing manifestations in storage.
EP 0 519 144 describes Omeprazole pellets consisting of an inert pellet core which is coded with the micronized active ingredient and is subsequently coated with a gastric juice-resistant layer. The following adjuvants, dispersed in water, are employed for coating the core with Omeprazole: hydroxymethylcellulose (HMC), water-free lactose, L-hydroxypropylcellulose (L-HPC), sodium lauryl sulfate, disodium hydrogen phosphate dihydrate. Hydroxypropylmethylcellulose phthalate (HPMCP) is used as a gastric juice-resistant coating. In this method, a possible reaction of the Omeprazole with the polymer is not excluded which can especially lead to a deteriorated storage stability.
EP 0 496 437 encompasses pellet cores and/or tablets which contain Omeprazole or an alkaline salt of Omeprazole together with an alkaline reacting compound (buffer) and which are coated with a layer of water-soluble, film-forming adjuvants which preferably react alkaline (buffer) as well as with a gastric juice-resistant outer film.
EP 0 239 200 uses basic magnesium salts and/or basic calcium salts for stabilizing benzimidazole derivatives with Omeprazole as typical representative.
According to this, numerous efforts were undertaken in the production of Omeprazole medicines which prevent the discoloration of the active ingredient, which considerably reduce the chemical degradation of Omeprazole, which prevent the degradation of the active ingredient in acidic gastric juice, but should simultaneously release the active ingredient as quickly as possible in the environment of the small intestine.
Object of the present invention is to provide an improved medicament as compared to the state of the art suitable for oral administration which comprises Omeprazole, Lansoprazole and/or Pantoprazole as an active ingredient, optionally in combination with further pharmaceutically effective substances, and which possesses-excellent stability in extended storage and under chemico-physical load. In particular, the penetration of acidic gastric juice into faults, cracks, chips or any other imperfections of the coating layer into the core layer should be avoided with the medicament according to the invention and the degradation of the acid-label active ingredient should be prevented therewith.
The medicament according to the invention guarantees a very high medicament security which above all should also be provided if unfavourable conditions arise in the course of the manufacturing process of the medicament as well as in the handling of the same and/or its packaged form by patients.
At the same time, it is necessary that the medicament quickly releases the active ingredient in the small intestine after passage through the stomach. Additionally, the degradation of the medicament should prevent the occurrence of discoloration of the active ingredient.
The above problem is solved according to the invention by a stable medicament for oral administration which                (a) comprises a core which contains an active ingredient selected from Omeprazole, Lansoprazole and Pantoprazole together with customary pharmaceutical adjuvants,        (b) an intermediate layer applied to the core, and        (c) a gastric juice-resistant outer layer,characterized in that a reactive intermediate layer of gastric juice-resistant polymer layer material-partially neutralized with alkali with cation exchange capacity is present in (b).        
Furthermore, subject-matter of the invention is a method for the production of the above-mentioned medicament, whereby                (a) a molded article is formed as the core which contains an active ingredient selected from Omeprazole, Lansoprazole and Pantoprazole, together customary pharmaceutical adjuvants,        (b) an intermediate layer is applied to the molded article, and        (c) the coated molded article is laminated with a gastric juice-resistant layer,and the method is characterized in that a reactive intermediate layer of a gastric juice-resistant polymer-coat material partially neutralized with alkali with cation exchange capacity is applied in (b).        
Preferred embodiments of the invention are given in the dependant claims.
The layer construction of the medicament according to the invention is schematically given in FIG. 1.
The core of the medicament according to the invention encompasses the active ingredient Omeprazole, Lansoprazole or Pantoprazole individually or combinations thereof together with customary auxiliary substances. For the stability of the medicament according to the invention it is not necessary and is also not preferred that the core of the active ingredient is formulated together with an alkaline reacting compound. It is also not necessary for an, alkaline salt of the active ingredient be employed.
As the pharmaceutical adjuvants for the core, fillers such as mannite, hydroxypropylcellulose, microcrystalline cellulose and water-free lactose are especially suitable. Additionally, it has be shown that advantageous stability effects can be obtained by using a specific combination of mannite and hydroxypropylcellulose as a non-alkalizing adjuvant in the core.
The core can also comprise tensides which are selected in the suitable manner from sodium lauryl sulfate, sorbitan fatty acid ester and polyoxyethylene sorbitan fatty acid ester.
The core of the medicament according to the invention can be formed as a molded article. Preferred molded articles are pellet cores, tablets microtablets or granulates.
The molded articles are coated with an intermediate layer. This intermediate layer preferably has a layer thickness of approximately 5 to 30 μm. It forms a mechanical as well as chemical barrier to the core. Thereby, it is necessary that the intermediate layer be present in an intact film. The polymer of the intermediate layer amounts to approximately 3 to 5% by weight of the core weight. The intermediate layer comprises a gastric juice-resistant polymer layer material which was adjusted with alkali to pH range of 5.5 to 7.0, preferably 5.5 to 6.5. With these pH values, not all protons of the acidic functions of the polymer material are exchanged; the material is merely partially neutralized. As emerges from FIG. 2, less than 40% of the carboxyl functions in the case of Eudragit® are present at a pH of 5.5. Despite this, a combination of Eudragit® partially neutralized to pH 5.5 with Omeprazole is unexpectedly stable even under intensive storage conditions (see Example 2). At pH 7.0, ca. 97% of the carboxyl functions of Eudragit® are neutralized (see FIG. 2).
As alkali substances, substances are to be understood whose solutions demonstrate alkaline reactions with water (Römpps Chemistry Encyclopaedia, 8th Edition, 1979). In this connection, hydroxides of alkali metals, especially sodium and potassium, but also hydroxides of the earth alkali metals are primarily among these. Hydroxides of the alkali metals, especially sodium hydroxide, are preferred according to the invention.
In the partial neutralization, protons of the acidic functions are fixed through the polymer chains of the coat material, for example carboxyl groups, are partially replaced by alkali metal ions for example as counter-ions. The polymer layer material modified in this manner is no longer physico-chemically inert in the presence of protons, but rather, is reactive because it now possess cation exchange capacity. This means that when moisture and especially acidic gastric juice penetrates into cracks, faults, chips or other imperfections through the outer layer of the medicament according to the invention, the penetrating protons are captured and are exchanged by harmless alkali metal ions. A further aspect of the reactive principal of the intermediate layer material is demonstrated by the fact the intermediate layer is transformed at these places into a gastric juice-resistant barrier; it possess a “self-repair-mechanism” to a certain degree. Practical tests have shown that with contact of the intermediate layer with an acidic medium forms a gel-like substance which not only captures protons but also forms a flexible mechanical barrier which prevents the further penetration of moisture and/or acid medium. The partial neutralization of the polymer material for the reactive intermediate layer to a pH range 5.5 to 6.5 is especially preferred because a gastric juice-resistant barrier already forms when only few protons penetrate through the outer layer; on the other hand, the Omeprazole core is still sufficiently stable.
Thereby, a clearly improved stability behaviour of the claimed medicament in extended storage and under chemico-physical load is also obtained.
Buffering and/or alkalizing additives in the intermediate layer as proposed in EP 0 247 983 are no longer necessary and can even be damaging because they increase solubility of the intermediate layer and reduce its protective function. This nearly contradicts the “self-repair-mechanism” according to the invention; namely, the more basic equivalents that are present in the intermediate layer, the more protons must penetrate from the outside so that the “self-repair-mechanism” of the reactive layer has a quick effect.
Eudragit® L100-55, Eudragit® L100 produced from Röhm-Pharma, Germany, as well as hydroxypropylmethylcellulose phthalate (HPMCP) and cellulose acetate phthalate (CAP) which, as described above, are partially neutralized with alkali before use as an intermediate layer, i.e. before spraying of the same, are suitable as preferred substances for the intermediate layer. Particularly preferred is Eudragit® L100-55 obtainable world-wide as a commercial product.
The intermediate layer can contain customary additives, for example an emollient. Preferably, triethyl citrate, acetyltriethyl citrate, acetylated monoglycerides, propylene glycol and polyethylene glycols are preferably suitable fore this.
The coated molded articles, i.e. the core and the intermediate layer, are then coated with an outer layer for the production of the medicament according to the invention. The outer layer represents a customary enteric; gastric juice-resistant layer. In this connection, commercial, aqueous polymer dispersions, such as polymethacrylates, for example Eudragit® L100-55 (Röhm Pharma), and coating CE 5142 (BASF) are suitable as materials. Additionally, polymers can also be used for formation of the gastric juice-resistant layer which are soluble in organic solvents. For example, phthalates (cellulose acetate phthalate, hydtoxypropylmethyl cellulose phthalate) are to be named as suitable materials. Additionally, the outer layer of the medicament according to the invention can contain antiblocking agents, dispersion agents, pigments and colorants. A suitable antiblocking agent is talcum for example.
In comparison to conventional medicinal forms with an inert intermediate layer, it was surprisingly determined that the inventive combination of enteric outer layer and reactive intermediate layer shows an accelerated dissolution behaviour in artificial intestinal fluid (pH ca. 5.8). This effect not only allows a very quick release of the active ingredient in the weakly acidic to weakly alkaline environment of the small intestine, and therewith an excellent bio-availability, but also permits improved medicament security because the enteric outer layer can be strengthened without retarding a desired quick release. Thereby, not only can the gastric juice-resistance be improved, but also the medicament stability especially under unfavourable storage conditions. Hence, the thickness of the gastric juice-resistant outer layer of the medicament according to the invention amounts to 2.0 to 60 μm (ca. 10 to 50% weight with respect to the core), preferably 30 to 60 μm.
In an advantageous embodiment of the invention, the reactive intermediate layer consists of partially neutralized Eudragit® L100-55 at a pH value of 5.5 to 7.0, preferably 5.5 to 6.5, and the outer layer consists of commercial Eudragit® L100-55 (pH ca. 2 to 3). The pH transition between outer layer and intermediate layer does not necessarily have to be discontinuous, but rather, can also be formed as a gradient, This can be obtained if several thin Eudragit layers are applied from inside to outside each of which was partially, neutralized to a decreasing pH value.
The reactive intermediate layer as well as the gastric juice-resistant outer layer can can be formed as a plurality of single layers.
The present invention further comprises a method for the production of a stable medicament for oral administration which comprises Omeprazole, Lansoprazole and/or Pantoprazole as an active ingredient.
According to the method of the invention, the active ingredient and adjuvants, such as mannite, hydroxypropylcellulose and sodium lauryl sulfate, are moistened together with a suitable solvent, preferably isopropanol, granulated and worked to the desired molded articles (for example pellets, granulates, tablets) according to customary methods. The molded articles are subsequently laminated with an aqueous dispersion consisting of a gastric juice-resistant substance partially neutralized with alkali to a pH value of ca. 5.5 to ca.7.0, preferably Eudragit® L100-55, as well as antiblocking agent and/or emollient, such as talcum and triethyl citrate, in a fluidized bed apparatus for example under formation of the intermediate layer with cation exchange activity. A quality product corresponding to Eudragit® L100-55 is also commercially obtainable as a finished suspension under the designation Eudragit® L30D-55. Subsequent to this, the coating occurs with a gastric juice-resistant substance (for example Eudragit® L100-55), talcum and an emollient (such as triethyl citrate) for formation of the enteric outer layer of the medicament according to the invention.
The production of pellets which are filled in gelatine capsules in an amount sufficient for the desired active ingredient dose is preferred.
Aside from the pellets containing the mentioned benzimidazole compounds, the capsule formulations produced in this manner can also contain other active ingredients. Preferable is a combination of Diclofenac- and Omeprazole-containing pellets. The Diclofenac-containing pellets are preferably produced according to the method of the invention, i.e. they also contain a reactive intermediate layer. However, they can also be produced by known methods, such as disclosed, in EP 0 348 808 for example. In a further embodiment, the Diclofenac-containing pellets are present as a mixture of gastric juice-resistant coated pellets and retarded permeable pellets which are first released in lower intestinal sections.
Combinations of non-steroidal inflammation inhibitors and analgesics are known. Thus, EP 0 527 887 names the combination of Diclofenac (o-(2,6-dichloroanilino)phenyl acetic acid), a highly effective NSAID (Non-Steroidal Anti-Inflammatory Drug), with Misoprostol, for example, which is employed for the treatment of painful inflammation diseases under the trade name Arthrotec®, Heumann Pharma GmbH, Germany. The prostaglandin derivative Misoprostol serves in this connection for prevention of NSAID-associated ulcer diseases.
The solid combination of Diclofenac and Omeprazole has a number of advantageous in long-term treatment of pain/inflammation. Thus, a combination of Diclofenac with Omeprazole maintains a low ulcer rate in patients who have a high risk for the development of gastrointestinal ulcers and who require treatment with an NSAID at the same time (ulcer prevention). Furthermore, this combination attains high ulcer healing rates in connection with sufficient pain relief (therapy). Patient compliance can be considerably increased as a result of the high effectiveness and good tolerance of the combination partners in connection with a single daily administration.
The capsule formulation which are suitable for direct administration per os comprise 25 to 200 mg, preferably 75 to 150 mg, Diclofenac and 10 to 40 mg, preferably 10 or 20 mg, Omeprazole as a unit dose in the pellets according to the invention.
The advantages of the medicament according to the invention with respect to Omeprazole and other benzimidazole-containing medicines of the art particularly exist in the fact that when any imperfections in the outer layer are present through which moisture upon storage or acidic gastric juice after peroral administration may penetrate into the core layer, the reactive intermediate layer not only captures protons but is additionally retransformed into a gastric juice-resistant layer material. Through this “self-repair-mechanism”, a gel-like layer is formed which is able to prevent the penetration of moisture and acid into the core of the medicament. In case that no penetration of gastric juice occurs, the intermediate layer remains soluble. Unexpectedly, the combination of enteric outer layer and the active intermediate layer additionally shows an improved dissolution behaviour in artificial intestinal fluid which infers a correspondingly good dissolution behaviour in the small intestine.
The invention is more closely illustrated by the following examples without limiting the invention to said examples.